Era Of Trials Research Articles

Response to induction chemotherapy modifies the effect of conventional prognostic factors in high-risk neuroblastoma: A report from the Children’s Oncology Group

BackgroundResponse to induction chemotherapy has been shown to predict outcome in patients with high-risk neuroblastoma (HR-NB), with those achieving a complete response (CR) having superior outcomes. MethodsWe evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. 1244 Patients from four COG high-risk trials were included. End-induction response was coded as CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Cox regression models were performed to calculate event-free and overall survival (EFS, OS) hazard ratios, including interaction terms between induction response and prognostic factors including sex, age, stage, primary tumor location, LDH, ferritin, ploidy, MYCN status, ALK status, histology, MKI, grade, and study era. ResultsAmong patients who achieved a CR after induction, INSS stage 4 disease and trial era were the only factors that remained significantly associated with inferior OS. For those who achieved less than a PR, adrenal primary site, MYCN amplification, and 1p LOH were associated with inferior outcomes. Multivariable models showed that end-induction response remained prognostic of EFS and OS even after controlling for other factors. Multiple significant statistical interactions were observed between end-induction response and other prognostic factors. ConclusionThe impact of conventional prognostic factors is not static in patients with HR-NB. Instead, response to induction chemotherapy modifies the effect of conventional prognostic factors. These data can help to further refine prognosis for patients with variable responses to induction and help to identify candidates who might benefit from treatment other than standard post-induction therapy.

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Clinical genetic testing in Parkinson's disease should become part of routine patient care.

This scientific commentary refers to ‘Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s Disease Study’ by Westenberger et al. (https://doi.org/10.1093/brain/awae188) and ‘Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study’ by Cook et al. (https://doi.org/10.1093/brain/awae142).

Pelvic Neuro-Visualization: An Anatomical Illustration of the Autonomic Pelvic Nervous Network in Gynecologic Surgery

ObjectiveDuring radical pelvic surgeries fibers of the autonomic pelvic nervous network can be accidentally damaged leading to significant visceral sequelae, which dramatically affect women's quality of life because of urinary, anorectal, and sexual postoperative dysfunctions.1,2 Direct visualization is one way to preserve hypogastric nerves (HNs), pelvic splanchnic nerves (PSNs), and the bladder branches from the inferior hypogastric plexus (IHP). However, the literature lacks critical photos and/or illustrations that are necessary to understand the precise anatomy needed to preserve the pelvic autonomic fibers. DesignNarrated laparoscopic video footage for identifying, dissecting, and preserving the autonomic nerve bundles during pelvic surgery. SettingTertiary level hospital—“IRCCS Istituto Nazionale dei Tumori”, Milano, Italy. InterventionsVisceral pelvic innervation is established by the superior hypogastric plexus(SHP) located anteriorly to the aortic bifurcation and the median sacral vessels and carries mostly sympathetic fibers. SHP divides in front of the sacrum into the right and left HN. At the level of the paracervix, the HNs join the parasympathetic PSNs coming out from sacral root S2, S3, S4 to form the IHP.2–5 Here, we performed laparoscopic surgery, before “Laparoscopic Approach to Cervical Cancer” trial (LACC) era, identifying key anatomic landmarks useful to highlight the path of the most commonly encountered autonomic pelvic nerves in gynecologic radical surgery: during the narration we describe and illustrate the procedure to identify all autonomic pelvic nerves, the sympathetic fibers, the PSNs, and the bladder branch emerging from the IHP in order to preserve their anatomic and functional integrity. This technique is anatomically and surgically indicated for adequate removal of the parametrical issues and vagina while preserving the total pelvic nervous system. ConclusionNerve-sparing surgery reduces bowel-, bladder- and sexual­ dysfunction without decreasing surgical efficacy.1,2 To accomplish safe and effective surgery, comprehension of the 3 dimensional structure of the vascular and nerve anatomy in the pelvis is essential. This video provides a great resource to educate surgeons, especially the youngest ones, about the retroperitoneal nervous networking: we identified the autonomic nerve pathway from adjacent tissues along the pathway consisting of cardinal, sacro-uterine, rectouterine/vaginal, and vesico-uterine ligaments.

Decompressive craniectomy for patients with malignant infarction of the middle cerebral artery: A pooled analysis of two randomized controlled trials

BackgroundDecompressive craniectomy (DC) reduces mortality without increasing the risk of very severe disability among patients with life-threatening massive cerebral infarction. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. It remains uncertain whether DC improves the prognosis of patients with malignant middle cerebral artery (MCA) infarction receiving endovascular therapy. MethodsWe pooled data from two trials (DEVT and RESCUE BT studies in China) and patients with malignant MCA infarction were included to assess outcomes and heterogeneity of DC therapy effect. Patients with herniation were dichotomized into DC and conservative groups according to their treatment strategy. The primary outcome was the rate of mortality at 90 days. Secondary outcomes included disability level at 90 days as measured by the modified Rankin Scale score (mRS) and quality-of-life score. The associations of DC with clinical outcomes were performed using multivariable logistic regression. ResultsOf 98 patients with herniation, 37 received DC surgery and 61 received conservative treatment. The median (interquartile range) was 70 (62-76) years and 40.8% of the patients were women. The mortality rate at 90 days was 59.5% in the DC group compared with 85.2% in the conservative group (adjusted odds ratio, 0.31 [95% confidence interval (CI), 0.10-0.94]; P=0.04). There were 21.6% of patients in the DC group and 6.6% in the conservative group who had a mRS score of 4 (moderately severe disability); and 10.8% and 4.9%, respectively, had a score of 5 (severe disability). The quality-of-life score was higher in the DC group (0.00 [0.00-0.14] vs 0.00 [0.00-0.00], P=0.004), but DC treatment was not associated with better quality-of-life score in multivariable analyses (adjusted β Coefficient, 0.02 [95% CI, -0.08-0.11]; p=0.75). ConclusionsDC was associated with decreased mortality among patients with malignant MCA infarction who received endovascular therapy. The majority of survivors remained moderately severe disability and required improvement on quality of life. Clinical Trial RegistrationThe DEVT trial: http://www.chictr.org. Identifier, ChiCTR-IOR-17013568. The RESCUE BT trial: URL: http://www.chictr.org. Identifier, ChiCTR-INR-17014167.

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

BackgroundPathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.MethodsPublished data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.ResultsWe established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.ConclusionsThese results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Optimising remote sampling of NfL and GFAP using blood cards in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort

AbstractBackgroundIn recent years, blood‐based biomarkers have become key measures in the study of dementia, including frontotemporal dementia (FTD), with use in diagnosis and clinical trial outcomes. Remote collection of blood samples provides a more accessible and cost‐effective alternative to regular clinic visits and allows for more frequent measures to be taken. This is particularly relevant as we progress into an era of clinical trials in FTD. The aim of this current study was to assess whether neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), markers previously shown be increased in genetic forms of FTD, can be measured using dried blood cards and to optimise the protocol for this.Method10 participants from the University College London GENFI study (three C9orf72 mutation carriers, four GRN mutation carriers and three mutation negative controls) were included in this pilot study. Blood samples were collected by venepuncture from each participant: one sample for plasma analysis and one sample which was used to pipette whole blood on to a blood card. NfL and GFAP concentrations were subsequently quantified using the Simoa multiplex Neurology 4‐Plex A (N4PA) assay in both plasma and the dried blood card. Total protein concentration was measured with the Bradford protein assay and used to correct for variable concentrations of blood card spots. The effect of incubation temperature and time as well as freeze thaw cycles were also assessed as part of the optimisation process.ResultIn this pilot cohort, blood card GFAP concentration (BSA corrected) very strongly correlated with matched plasma GFAP (r = 0.897, p = 0.0004), whilst blood card NfL concentration (BSA corrected) strongly correlated with matched plasma NfL (r = 0.721, p = 0.0234). Incubation temperature impacted total protein concentration in the blood cards, but freeze‐thaw and incubation time did not.ConclusionThis pilot study shows that NfL and GFAP concentrations can be successfully quantified using dried blood cards and results strongly correlate with plasma measures. Future work will involve investigating whether these biomarkers can be measured in blood cards obtained with capillary blood through lancet‐based fingerprick collection and assessing the feasibility of home collection.

Abstract 17504: Revisiting the Etiology of a Non-Ischemic Cardiomyopathy

Introduction: In the era of REVIVED-BCIS2 and ISCHEMIA clinical trials, the role of routine invasive coronary angiography for treatment of coronary artery disease (CAD) in the setting of left ventricular dysfunction has come into question. While the majority of heart failure (HF) patients undergo some form of non-invasive ischemic evaluation, there are a wide range of opinions on which testing modality is the most appropriate. Case: This is a 53 year-old man with a history of HTN, HLD, and presumed non-ischemic cardiomyopathy and LVEF of 15-20%, first diagnosed in 2009. He had a family hx of heart disease in several distant relatives, thus the etiology was presumed familial. In 2022, he had NYHA class II symptoms and a routine echo showed a LVEF of 25% with anteroseptal hypokinesis. Given these findings, a coronary CTA was obtained. This demonstrated infarct in the LAD territory and a proximal left main to mid-LAD aneurysm measuring up to 7 mm with a partially calcified shell and peripheral thrombus, consistent with prior Kawasaki’s disease (KD). He was initiated on a DOAC to prevent further embolic events and aspirin. He is now undergoing serial monitoring of the aneurysm size, thrombus burden, and functional testing to monitor for ischemia. Discussion: Non-invasive anatomic testing to evaluate for CAD in HF patients can provide useful information over a functional assessment. KD is a rare disease with an estimated incidence rate of ≈25 per 100,000 children less than 5 years of age. KD can lead to coronary artery aneurysms, which often contain thrombi, and subacute/chronic myocarditis. The affected arteries can become stenotic over time or even occlude, leading to ischemic injury later in life. Early recognition of this rare disease is important to initiate appropriate treatment and prevent thromboembolic complications. Conclusion: KD is a rare cause of adult cardiomyopathy. Anatomic testing was essential to appropriately diagnose and treat this patient’s cardiomyopathy.

The Audacity of Judging Mind in Medieval England

In medieval English texts, a common refrain, drawn from scripture, urged that only God could search the mind and heart of a sinner, and that those who judge others might face their own grave judgment on the last day. This sits uneasily with the task of issuing a felony verdict, a burden placed squarely upon the shoulders of lay jurors after the Fourth Lateran Council's effective abolition of trial by ordeal in 1215. Nevertheless, jurors did sit in judgment upon their neighbors, and evidence suggests that they were not merely assessing outward conduct but also the state of a defendant's heart and mind which, like the hand of a proband in the era of trial by ordeal, might be declared fair or foul. This essay explores how techniques for unearthing intentionality through circumstantial inquiry—techniques developed in the context of classical rhetoric and adapted for priests hearing confessions—were put to use by coroners and others tasked with investigating crimes. This, in turn, aided jurors in the perilous, even audacious, task of judging alleged felons, ultimately determining who should be acquitted and who should face the gallows.

Thrombectomy Use in the United States for Basilar Artery Occlusion in the Era of Neutral Clinical Trials: 2018 to 2020 Analysis of the National Inpatient Sample

Background In 2019 and 2020, 2 randomized trials of basilar artery occlusion (BAO) thrombectomy reported no improvement in functional outcomes with thrombectomy, despite observational evidence. The objective of this study was to assess whether neutral clinical trials may have influenced BAO thrombectomy practice. Methods The National Inpatient Sample (2018–2020) was queried for US patients with BAO, and comparisons were made between patients admitted in 2020 versus 2018 to 2019 for the primary outcome of thrombectomy. Unadjusted and adjusted multivariable regression was used, accounting for demographic and clinical covariates, with propensity‐score matching to balance clinical and hospital‐level characteristics between years. Results Of the 14 945 patients with BAO, 3,605 (24.1%) underwent thrombectomy,with an increase in the unadjusted rate of thrombectomy between 2020 and 2018–2019 (26.9% vs 22.9%, P = 0.04). Following multivariable adjustment, BAO thrombectomy was not independently associated with a year of treatment (adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 0.95–1.54, P = 0.12). Thrombectomy was independently associated with having a NIHSS of 10–19 (OR: 3.67, 95% CI: 2.79–4.83, P < 0.01) or >19 (OR: 5.80, 95% CI: 4.41–7.64) versus a NIHSS of 10, while uinsured patiends hadal owe likelihood of receiving a thombectomy (OR: 0.49, 95% C: 0.26–0.92). These relationships were preserved in the PSM cohort, and admission year lacked association with thrombectomy for BAO (aOR: 1.10, 95% CI: 0.83–1.45, P = 0.52). Conclusion Following publication of neutral BAO randomized clinical trials in late 2019 and 2020, there was no significant change in thrombectomy rate among US patients with BAO. The latest trials support thrombectomy for select patients with moderate‐to‐severe BAO symptoms, and this appears consistent with the practice of US clinicians before these trials.

Precise, pragmatic and inclusive: the modern era of oncology clinical trials.

Precise, pragmatic and inclusive: the modern era of oncology clinical trials.

Co-Clinical Imaging Metadata Information (CIMI) for Cancer Research to Promote Open Science, Standardization, and Reproducibility in Preclinical Imaging.

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

Impact of Decompressive Craniectomy on Hemorrhagic Transformation in Malignant Ischemic Stroke in Mice.

Endovascular thrombectomy has changed the management of ischemic stroke. The reperfusion can however lead to a hemorrhagic transformation (HT). Decompressive craniectomy (DC) is a surgical procedure used for malignant ischemic stroke. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. Here, we hypothesized that DC for ischemic stroke after thrombectomy could lead to a higher risk of HT. We thus evaluated this hypothesis in a mouse model of stroke induced by occlusion of the middle cerebral artery (MCAO) with or without mechanical reperfusion. Ninety mice subjected to MCAO were divided into 6 groups: permanent MCAO with or without DC; MCAO followed by a mechanical reperfusion with or without DC and MCAO with a mechanical reperfusion followed by r-tPA (recombinant tissue-type plasminogen activator)-induced reperfusion with or without DC. Mice were evaluated by magnetic resonance imaging 24 hours after the MCAO to assess ischemic lesion volumes, and the rate, type, and volume of HTs. The ischemic volume was higher in the 2 groups without reperfusion than in the 4 groups with reperfusion independently of r-tPA treatment and DC. The distribution of HT types was different between the 6 groups. The HT volumes and HT scores was smaller in the 2 groups without reperfusion and in the reperfusion group without r-tPA and without DC. In mice having reperfusion, the mean HT score was higher in mice who had DC without r-tPA (HT score 5; P=0.048) or with r-tPA (HT score 8; P=0.02), than in mice without DC (HT score 1). DC for a malignant stroke, after reperfusion, corresponding to an endovascular thrombectomy failure, increases the risk of severe hemorrhagic transformations in a model of ischemic stroke in mice. This result support the need of clinical studies to evaluate the added value of DC at the era of endovascular thrombectomy.

Systemic therapy for early-stage breast cancer: learning from the past to build the future.

The treatment of breast cancer has improved dramatically over the past century, from a strictly surgical approach to a coordinated one, including local and systemic therapies. Systemic therapies for early-stage disease were initially tested against observation or placebo only in adjuvant trials. Subsequent clinical trials focusing on treatment ‘fine-tuning’ had a marked increase in cohort size, duration and costs, leading to a growing interest in the neoadjuvant setting in the past decade. Neoadjuvant trial designs have the advantages of enabling the direct evaluation of treatment effects on tumour diameter and offer unique translational research opportunities through the comparative analysis of tumour biology before, during and after treatment. Current technologies enabling the identification of better predictive biomarkers are shaping the new era of (neo)adjuvant trials. An urgent need exists to reinforce collaboration between the pharmaceutical industry and academia to share data and thus establish large databases of biomarker data coupled with patient outcomes that are easily accessible to the scientific community. In this Review, we summarize the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era and provide critical insights into how neoadjuvant studies are currently designed, discussing the need for better end points and treatment strategies that are more personalized, including in the post-neoadjuvant setting.

Metformin and type 2 diabetes in the era of cardiovascular outcome trials; A narrative review

Metformin has been for many years the first-line pharmaceutic treatment for most patients with type 2 diabetes. However, new classes of antidiabetic agents with proven cardiorenal benefits beyond glycemic control challenge metformin’s predominance. The hypoglycemic effect of metformin is mediated in liver by inhibiting gluconeogenesis and improving insulin sensitivity and in intestines by reducing glucose absorption, increasing incretins and altering intestinal microbiome. After decades of use metformin has been proved to be one of the most potent, safe and cost-effective medications for the treatment of type 2 diabetes. Several other pleiotropic actions of metformin in inflammation pathways suggest a potential cardioprotective role. This hypothesis has been tested in a few randomized trials and in more observational studies and metanalyses with controversial results. Given the lack of robust evidence for the cardioprotective effect of metformin compared to the newer antidiabetic agents, current treatment algorithms are under scrutiny. Ongoing randomized clinical trials comparing metformin to placebo are expected to elucidate the effect of metformin on specific cardiovascular and renal outcomes.

Correction to: Non-invasive Assessment of the Coronary Arteries in the Era of the ISCHEMIA Trial

Correction to: Non-invasive Assessment of the Coronary Arteries in the Era of the ISCHEMIA Trial

Non-invasive assessment of the coronary arteries in the era of the ISCHEMIA trial

Non-invasive assessment of the coronary arteries in the era of the ISCHEMIA trial

Increase in Ruptured Cerebral Arteriovenous Malformations and Mortality in the United States: Unintended Consequences of the ARUBA Trial?

Background The findings of the ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformation) trial, which determined that medical management was superior to prophylactic interventional therapy for the treatment of unruptured cerebral arteriovenous malformations (cAVMs), remain polarizing and controversial. Methods Adult cAVM patient admissions were identified in the National Inpatient Sample from 2009 to 2019. The incidence of cAVM rupture and in‐hospital mortality were compared between the pre‐ (2009–2013) and post‐ARUBA trial eras (2014–2019) using complex samples‐weighted estimates and multivariable logistic regression analyses. A control cohort composed of an alternate pathology (ruptured and unruptured cerebral aneurysms) was also assessed during the study period to evaluate potential bias. Results Among 121 415 hospitalizations for cAVM during the study period, 31 389 (25.9%) were admissions for ruptured malformations. The incidence of ruptured cAVM increased in the post‐ARUBA trial era (13.3% versus 34.4%; P <0.001) as well as rates of in‐hospital mortality (2.0% versus 7.6%; P <0.001). Following multivariable regression analysis adjusting for age, illness severity, and acute neurological condition, the post‐ARUBA trial era was independently associated with both cAVM rupture (adjusted odds ratio [OR], 1.99; [95% CI, 1.72–2.29]; P <0.001) and in‐hospital mortality (adjusted OR, 1.94; [95% CI, 1.37–2.75]; P <0.001). Control cohort comparative analysis revealed that rates of hospitalizations for ruptured cerebral aneurysms relative to all aneurysm admissions did not differ before and after 2014 (84.5% versus 84.3%; P =0.185). Conclusion The incidence of ruptured cAVM increased following 2014, potentially a reflection of a paradigm shift to conservative and noninterventional management strategies in patients with unruptured cAVM. Further studies may be necessary to exclude other confounders contributing to this rise.

Neoadjuvant Therapy in the Post–German Rectal Trial Era: Making Sense in the Absence of Consensus

Trimodality therapy per the German Rectal Trial has led to excellent locoregional outcomes for locally advanced rectal cancer. Recent efforts have shifted toward improving distant control and health-related quality of life in this disease. To this end, total neoadjuvant therapy has become an increasingly used approach in which most, if not all, chemotherapy is delivered before surgery to improve compliance and to address micrometastases early. To avoid surgical morbidity, a “watch-and-wait” approach, in which total mesorectal excision is deferred, has also been studied for patients who achieve a clinical complete response after chemoradiation. These 2 concurrent treatment trends have raised many points of uncertainty in what used to be a relatively straightforward neoadjuvant treatment paradigm. We discuss here our approach to neoadjuvant therapy for locally advanced rectal cancer, based on the data we currently have and through shared decision-making with patients to help them select the treatment that best aligns with their preferences and values.

Saccular aneurysms in the post-Barrow Ruptured Aneurysm Trial era.

The Barrow Ruptured Aneurysm Trial (BRAT) was a single-center trial that compared endovascular coiling to microsurgical clipping in patients treated for aneurysmal subarachnoid hemorrhage (aSAH). However, because patients in the BRAT were treated more than 15 years ago, and because there have been advances since then-particularly in endovascular techniques-the relevance of the BRAT today remains controversial. Some hypothesize that these technical advances may reduce retreatment rates for endovascular intervention. In this study, the authors analyzed data for the post-BRAT (PBRAT) era to compare microsurgical clipping with endovascular embolization (coiling and flow diverters) in the two time periods and to examine how the results of the original BRAT have influenced the practice of neurosurgeons at the study institution. In this retrospective cohort study, the authors evaluated patients with saccular aSAHs who were treated at a single quaternary center from August 1, 2007, to July 31, 2019. The saccular aSAH diagnoses were confirmed by cerebrovascular experts. Patients were separated into two cohorts for comparison on the basis of having undergone microsurgery or endovascular intervention. The primary outcome analyzed for comparison was poor neurological outcome, defined as a modified Rankin Scale (mRS) score > 2. The secondary outcomes that were compared included retreatment rates for both therapies. Of the 1014 patients with aSAH during the study period, 798 (79%) were confirmed to have saccular aneurysms. Neurological outcomes at ≥ 1-year follow-up did not differ between patients treated with microsurgery (n = 451) and those who received endovascular (n = 347) treatment (p = 0.51). The number of retreatments was significantly higher among patients treated endovascularly (32/347, 9%) than among patients treated microsurgically (6/451, 1%) (p < 0.001). The retreatment rate after endovascular treatment was lower in the PBRAT era (9%) than in the BRAT (18%). Similar to results from the BRAT, results from the PBRAT era showed equivalent neurological outcomes and increased rates of retreatment among patients undergoing endovascular embolization compared with those undergoing microsurgery. However, the rate of retreatment after endovascular intervention was much lower in the PBRAT era than in the BRAT.